Schmidt-Kittler et al. (2003) now present evidence that further challenges the clonal-progression-to-metastasis paradigm. Their study is based on comprehensive genomic analyses of primary breast tumors and single cytokeratin-positive (CK+) epithelial cells from the bone marrow of these same patients. Patients were selected that had no evidence of metastatic disease (UICC stage M0) or had metastasized (UICC stage M1). Previous publications have shown that CK+ cells originate in the tumor and their presence is associated with increased propensity to develop metastatic disease Braun et al. 2000, Pantel et al. 1999. The CK+ cells and cells from the corresponding primary tumors were analyzed for loss of heterozygosity and genome copy number using comparative genomic hybridization as described earlier (Klein et al., 1999). The CK+ cells from M0 patients showed approximately half as many genomic aberrations as those from M1 patients. Surprisingly, most of the CK+ cells from M0 patients showed little resemblance to the primary tumors from which they presumably arose. Schmidt-Kittler et al. reasoned that this might be because the disseminated cells separated from the tumor quite early—perhaps before telomere crisis. To explore this, they compared the genomic abnormalities in disseminated cells from M0 and M1 patients. Cells from M0 patients showed whole chromosome copy number aberrations while cells from M1 patients showed subchromosomal changes characteristic of aberrations that form during telomere crisis. They attribute the eventual development of metastatic disease in M0 patients to these early disseminated cells. They suggest that these cells transition through crisis independently from cells in the primary tumor and evolve independently of the primary tumor. The long-term persistence and slow evolution of these disseminated cells would explain why metastatic disease sometimes develops years after apparently successful treatment of the primary tumor
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